Bladder Cancer
Margaret A. Knowles
Understanding of the molecular changes that underlie bladder cancer development has progressed rapidly.1,2,3,4 Most studies have focused on urothelial carcinomas (UCs), which comprise the majority (>90%) of tumors diagnosed in the Western world. Where the parasite Schistosoma haematobium is endemic, squamous tumors predominate, and there is evidence that these differ at the molecular level.5,6 This chapter will focus on somatic alterations identified in UC by genomic and RNA profiling. There is also much information about germline polymorphisms that confer increased risk of UC development and the reader is referred to recent reviews on this topic.7,8,9
At diagnosis more than 70% of UCs are noninvasive (Ta) or superficially invasive (T1) papillary lesions. These commonly recur, but progression to muscle invasion is infrequent (10% to 20%) and prognosis is good. In contrast, tumors that are muscle invasive at diagnosis (≥T2) have poor prognosis (<50% survival at 5 years). Carcinoma in situ (CIS) is a high-grade lesion, that is “superficial” in the strict sense, but has poor prognosis. It is not yet clear whether, or how often, papillary low-grade tumors become invasive. This has led to an ongoing debate, which is as yet unresolved.1 The divergent behavior of these tumor groups is reflected in striking differences in their molecular profiles.1,2,3,4
MOLECULAR ALTERATIONS IN SUPERFICIAL UROTHELIAL CARCINOMA
Low-grade Ta papillary UCs are genetically stable and commonly contain point mutations or loss of entire chromosomes of chromosome arms rather than complex chromosomal rearrangements. Recent findings also indicate significant alteration or microRNA (miRNA) expression. Common alterations are deletions of chromosome 9 (>50%), mutations of FGF receptor 3 (FGFR3), and mutations of the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K) (PIK3CA) (Table 21.1). These tumors are often near diploid. Loss of heterozygosity (LOH) of 11p is found in approximately 40% of UCs, including some Ta tumors, but is more common in tumors of higher grade and stage. Gains of 1q, 17, and 20q, amplifications of 11q, and loss of 10q have been identified but are not common (Table 21.1). Amplifications of 11q include the cyclin D1 gene (CCND1), which is involved in cell-cycle progression from G1 to S phase (Fig. 21.1).
Promoter hypermethylation of APC, CDKN2A (p14ARF), and RASSF1A has been found in DNA from urine of bladder cancer patients including those with low-grade/stage tumors.10 However, this is more common in tumors of high tumor grade and stage.11 Some hypermethylation in Ta/T1 tumors is associated with increased risk of progression.12 A study that related regional gene expression to DNA copy number, identified genomic regions with altered expression that were copy number-independent, most showing down-regulation. Genes known to show promoter methylation in UC were not located in these regions, indicating other mechanisms of gene silencing.13
Low-grade Ta tumors are genetically stable. Thus, synchronous or metachronous tumors from the same patient show great genetic similarity, although some clonal evolution can be detected over time. LOH of chromosome 9 and mutation of FGFR3 are the least divergent events, and widely believed to represent early genetic changes.14,15 Flat urothelial hyperplasia, a predicted tumor precursor, shows more frequent chromosome 9 loss than FGFR3 mutation, suggesting that this occurs earlier.16
Chromosome 9
More than 50% of UCs of all of grades and stages show chromosome 9 LOH, many with loss of an entire homologue.17,18,19 A critical region on 9p21 and at least three regions on 9q (9q22, 9q32-q33, and 9q34) have been identified. Candidate genes within these regions are CDKN2A (p16/p14ARF) and CDKN2B (p15) at 9p21,20,21,22,23,24 PTCH (Gorlin syndrome gene) at 9q22,25,26 DBC1 at 9q32-q33,27,28,29
and TSC1 (tuberous sclerosis syndrome gene 1) at 9q3430,31,32,33 (Table 21.1).
and TSC1 (tuberous sclerosis syndrome gene 1) at 9q3430,31,32,33 (Table 21.1).
TABLE 21.1 GENETIC CHANGES IDENTIFIED IN Ta BLADDER TUMORS | |||||||||||||||||||||||||||||||||
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CDKN2A (9p21) encodes the two cell-cycle regulators, p16 and p14ARF, which share coding region in exons 2 and 3 but have distinct exons 1. The protein products are translated in different reading frames to generate two entirely different proteins. p16 is a negative regulator of the Rb pathway and p14ARF, a negative regulator of the p53 pathway (Fig. 21.1). Inactivation of this locus in UC is commonly by homozygous deletion (HD). There are conflicting reports on association of 9p21 deletion with clinical parameters but HD appears to be associated with high tumor grade and stage.34 Reduced copy number of 9p21 is present in approximately 45% of UC, indicating that, as suggested by knockout mice and in vitro experiments.35,36 p16 and/or p14ARF may be haploinsufficient.34
On 9q, three genes are implicated. PTCH, the Gorlin syndrome gene (9q22) shows infrequent mutation,26 but many tumors have reduced mRNA expression.25 DBC1 (9q33) shows HD in a few tumors29,37 and no mutations, but is commonly silenced by hypermethylation.27,38 LOH of 9q34 and mutation of the retained copy of TSC1 is found in approximately 13% of UC.39 The protein acts in complex with the TSC2 protein to negatively regulate mTOR, a central molecule in the control of protein synthesis and cell growth (Fig. 21.2).
FGFR3
Since the initial identification of FGFR3 mutations in UC,40 11 different mutations have been identified.41,42,43,44,45,46,47,48,49,50,51,52,53,54 These are in hot-spot codons in exons 7, 10, and 15 (Fig. 21.3A) and are all predicted to constitutively activate the receptor.55 Mutation is associated with low tumor grade and stage, with up to 80% of low-grade Ta tumors showing mutation.42 Mutations are also found in urothelial papilloma, a likely precursor of superficial UC.50 Mutation is not associated with tumor recurrence or progression in Ta tumors overall,43,54,56 but there is evidence that mutant Ta grade 1 tumors show a higher risk of recurrence.43 Tumors with FGFR3 mutation show increased FGFR3 protein expression, as do a significant number of tumors without mutation.57
Mutant FGFR3 proteins are oncogenic in rodent mesenchymal cells.58,59 In cultured normal urothelial cells, mutant FGFR3 activates
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